Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Wellcome Trust Sanger Institute, University of Cambridge, Hinxton CB10 1SA, UK.
Science. 2014 Mar 7;343(6175):1246949. doi: 10.1126/science.1246949.
To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.
为了系统地研究免疫刺激对调节变异体活性的影响，我们将来自 432 名健康欧洲人的原代单核细胞暴露于干扰素-γ（IFN-γ）或不同时间的脂多糖中，并绘制了表达数量性状基因座（eQTLs）图谱。鉴定出的超过一半的顺式-eQTLs，涉及数百个基因和相关途径，仅在受刺激的单核细胞中检测到。诱导的先天免疫活性揭示了多个主调控转录 eQTL，包括主要组织相容性复合体（MHC）、改变酶和受体功能的编码变异体、具有时间特异性的 IFN-β细胞因子网络以及干扰素调节因子 2（IRF2）转录因子调节网络。诱导的 eQTL 显著富集了全基因组关联研究（GWAS）位点，确定了与推定的因果基因（包括 CARD9、ATM 和 IRF8）的特定于上下文的关联。因此，应用生理相关的免疫刺激有助于解决功能遗传变异体的问题。
